The present invention relates to novel antibodies, in particular murine monoclonal antibodies, chimeric and humanized, able to bind specifically interleukin IL-34 as well as the amino and nucleic acid sequences coding for such antibodies. From one aspect, the invention relates to novel antibodies or an antigen fragments thereof, able to bind specifically to the IL-34. The invention also comprises the use of such antibodies or an antigen fragments thereof as a medicament for the preventive and/or therapeutic treatment of diseases involving IL-34.
In 2008, a new cytokine named interleukin-34 (IL-34) was discovered by Lin et al. based on its ability to induce the formation of colony-forming unit-macrophages in human bone marrow cultures, with the same efficiency as Macrophage Colony Stimulating Factor (M-CSF) (Lin et al., 2008). IL-34 bind in a close way to the extracellular domain of CSF-1 receptor (M-CSFR), but with a different binding mode of M-CSF (Felix et al., 2013; Ma et al., 2012) leading to receptor dimerization and differential autophosphorylation on its eight tyrosine residues.
More recently, Wang et al. reported that IL-34 was a specific driver of myeloid cell differentiation in the skin epidermis and central nervous system (Wang et al., 2012). IL-34 also directs the differentiation of monocytes into immunosuppressive M2 similar to M-CSF (Foucher et al., 2013). In addition, it was demonstrated, that IL-34 is expressed by giant cell tumours of bone and can be a substitute for M-CSF in promoting osteoclastogenesis (Baud'huin et al., 2010). IL-34, like M-CSF, upregulates the chemokines produced by whole blood, identifying both cytokines as key partners in inflammation (Eda et al., 2010). The role of IL-34 was also confirmed in rheumatoid arthritis.
Furthermore, IL-34 is involved in some cancers such as osteosarcoma, Ewing's sarcoma, bone tumors, brain cancer, in skin diseases and in metabolic diseases such as atherosclerosis (Ségaliny et al., 2014, Stanley et al., 2014, Wang et al., 2014 and Cronk et at., 2013). The majority of these effects of IL-34 are mediated by M-SFR. 11-34 also plays a singular role that has recently been explained in the brain through a binding to the receptor protein tyrosine phosphatase RPTPβ/ζ.
Thus, it is important to have means regulating the interaction between 11-34 and its receptor.
The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Such therapeutics function through mediating alterations in antigen or receptor function, modulating the immune system or delivering a specific drug that is conjugated to an antibody that targets a specific antigen.
A monoclonal antibody Rg7155 inhibiting CSF-1 receptor dimerization was previously described. The administration of this antibody to the patient led to striking reductions of CSF-1R+CD163+ macrophage infiltrations in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor patients (Ries et al., 2014).
However this antibody is nonspecific since it inhibits similarly both M-CSF and IL-34 binding.
An anti-IL-34 antibody is also described in WO 2013/119716. This antibody is capable of binding IL-34 and thus blocking the interaction between IL-34. This antibody is capable of binding of inhibiting the signalization pathway mediated from the binding of IL-34 to its receptor. Moreover, it is used in for treating some immunological diseases.
Furthermore, WO 2013/119716 discloses that said antibody anti-IL-34 has a binding affinity to its ligand IL-34 comprised between 1.7×10−8 and 1.24×10−10 which is said to seem to be a good affinity.
However, it is well known in the art that the strength of binding affinity of an antibody to its target is very important criteria for selecting therapeutically effective antibodies.
There is thus still a need for novel antibodies specifically targeting IL-34 and having a very strong binding activity for its target, which could be used for efficiently treating autoimmune diseases and cancer.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.